Scientists at St. Jude Children's Research Hospital have shown in that it might be possible to make tumor cells more sensitive to irradiation and some types of chemotherapy by treating them with a drug that cripples their ability to repair DNA damage caused by these therapies.

The St. Jude researchers demonstrated in the laboratory that a molecule called CP466722 rapidly blocks the ATM protein's ability to orchestrate a series of biochemical events that culminate in the repair of DNA damaged by irradiation. The molecule exerted its effect in small quantities, and its effects rapidly ended after it was removed from cells, suggesting that such a treatment in humans would not have significant or long-term side effects, the researchers said.

Results of the study were published in the Sept. 15, 2008 issue of the journal Cancer Research.

ATM plays a critical role in repairing a type of DNA damage called double-strand breaks, in which each of the two strands making up this molecule are cut, according to Michael Kastan, M.D., Ph.D., director of the St. Jude Comprehensive Cancer Center. This process protects cells from the potentially lethal or mutation-causing effects of free oxygen radicals and irradiation-both of which routinely threaten them, he added. Kastan is senior author of the report on these findings.

Children lacking the gene for ATM develop ataxia-teleangiectasia, a disease that causes several debilitating problems, such as neurodegeneration, cancer and sensitivity to irradiation that leads to irreparable, double-stranded DNA breaks.

"We found that inhibition of ATM activity with CP466722 produces cellular effects that are identical to those seen in cells that lack ATM," Kastan said. "It's as if we temporarily turned normal cells into cells indistinguishable from those of children with ataxia-telangiectasia."

The protective role of ATM makes it a tempting target for researchers looking for a way to prevent cancer cells from repairing DNA damage caused by therapeutic irradiation, Kastan noted.

Previously Kastan's team found how ATM is activated by a signal from damaged DNA only seconds after the damage occurs. The activated ATM, in turn, activates other proteins by attaching a molecule called phosphate to them in a process called phosphorylation. This sets off a cascade of biochemical reactions that amplifies the initial ATM response leading to repair of the double-stranded break.

"Our ability to rapidly and reversibly regulate ATM activity with CP466722 also gives us a new tool to study the function of this protein, which plays such a critical role in the ability of both normal and cancerous cells to repair their DNA," said Michael Rainey, Ph.D., a postdoctoral fellow in the St. Jude Department of Oncology. "This approach will help us learn more about the repair events triggered by ATM in response to DNA damage." Rainey is the report's first author.

Kastan also noted that CP466722 provides his team with a basic chemical structure that they can build upon as they try to modify the molecule to enhance its potency and specificity and move studies from isolated cells to mouse models.

"Results of those mouse model studies would help us to determine if and how to proceed with studies in patients with cancer," Kastan said.

The St. Jude researchers demonstrated in isolated cells that irradiation activated ATM, which in turn triggered the normal cascade of biochemical events that repaired broken DNA, and that CP466722 inhibited all of these events. This occurred not only in standard laboratory cells called HeLa cells, but also in human breast cancer cells. Overall, the response to CP466722 in irradiated cells was similar to that seen in cells lacking ATM, the team reported. The researchers also showed that CP466722 sensitized mouse cells to irradiation, an important finding since the team plans to study this effect in those models.

Finally, the team showed that exposure of HeLa cells to CP466722 for only four hours inhibits ATM sufficiently to enhance the cell's sensitivity to irradiation, and that after the compound's removal, the inhibition was rapidly and completely reversed. This suggested that a drug based on CP466722 might enable clinicians to treat patients with minimal doses for brief periods to achieve the maximum therapeutic effect.

Other authors of this report include Maura Charlton and Robert V. Stanton (Pfizer Research Technology Center, Pfizer Global Research and Development, Cambridge, Mass.).

This work was supported by Pfizer, the National Institutes of Health and ALSAC.

St. Jude Children's Research HospitalSt. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org/.

About Cancer

Cancer (medical term: malignant neoplasm) is the general name for a group of more than 100 diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.

Cancer cells can spread to other parts of the body through the blood and lymph systems. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer that begins in basal cells of the skin is called basal cell carcinoma.

Cancer types can be grouped into broader categories. The main categories of cancer include:

Carcinoma - a cancer which is derived from the lining cells, or epithelium, of an organ. There are 4 major types of epithelium in the body (Glandular, squamous, transitional, and pseudostratified). Some types are only found in a few select organs such as the lung (pseudostratified) or urinary bladder (transitional). Carcinomas can arise from any of these epithelial types. For example, breast carcinoma is most commonly derived from the lining cells of the milk producing glands. A carcinoma with a glandular growth pattern is an adenocarcinoma. Common adenocarcinomas include prostate, colon, and breast. A carcinoma with a growth pattern resembling the squamous lining cells is termed a squamous cell carcinoma. Common squamous cell carcinomas are found in the esophagus and skin. However, any of these organs may have either type of carcinoma arising from it, although these latter diagnoses are exceedingly rare.

Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord.

Leukemia - cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood.

Lymphoma - a cancer derived from the white blood cells that are present in the lymphoid tissues of the body. These sites most commonly include the lymph nodes and spleen. However, lymphomas may arise from any organ and body site.

Today, millions of people are living with cancer or have had cancer. The risk of developing most types of cancer can be reduced by changes in a person's lifestyle, for example, by quitting smoking, limiting time in the sun, being physically active, and eating a better diet. Half of all men and one-third of all women in the US will develop cancer during their lifetimes.

Although doctors often cannot explain why one person develops cancer and another does not, research shows that certain risk factors increase the chance that a person will develop cancer. Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or viruses, bacteria, and certain hormones. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. Other common risk factors for cancer include: